Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.
National Cancer Center Research Institute, Tokyo, Japan.
FEBS J. 2022 Dec;289(24):7987-8002. doi: 10.1111/febs.16180. Epub 2021 Sep 16.
Homeostasis in the blood system is maintained by the balance between self-renewing stem cells and nonstem cells. To promote self-renewal, transcriptional regulators maintain epigenetic information during multiple rounds of cell division. Mutations in such transcriptional regulators cause aberrant self-renewal, leading to leukemia. MOZ, a histone acetyltransferase, and MLL, a histone methyltransferase, are transcriptional regulators that promote the self-renewal of hematopoietic stem cells. Gene rearrangements of MOZ and MLL generate chimeric genes encoding fusion proteins that function as constitutively active forms. These MOZ and MLL fusion proteins constitutively activate transcription of their target genes and cause aberrant self-renewal in committed hematopoietic progenitors, which normally do not self-renew. Recent progress in the field suggests that MOZ and MLL are part of a transcriptional activation system that activates the transcription of genes with nonmethylated CpG-rich promoters. The nonmethylated state of CpGs is normally maintained during cell divisions from the mother cell to the daughter cells. Thus, the MOZ/MLL-mediated transcriptional activation system replicates the expression profile of mother cells in daughter cells by activating the transcription of genes previously transcribed in the mother cell. This review summarizes the functions of the components of the MOZ/MLL-mediated transcriptional activation system and their roles in the promotion of self-renewal.
血液系统中的内稳定是通过自我更新干细胞和非干细胞之间的平衡来维持的。为了促进自我更新，转录调节因子在多次细胞分裂过程中维持表观遗传信息。这种转录调节因子的突变导致异常的自我更新，导致白血病。MOZ，一种组蛋白乙酰转移酶，和 MLL，一种组蛋白甲基转移酶，是促进造血干细胞自我更新的转录调节因子。MOZ 和 MLL 的基因重排产生编码融合蛋白的嵌合基因，这些融合蛋白作为组成型激活形式发挥作用。这些 MOZ 和 MLL 融合蛋白组成型激活其靶基因的转录，并导致通常不自更新的定向造血祖细胞的异常自我更新。该领域的最新进展表明，MOZ 和 MLL 是转录激活系统的一部分，该系统激活具有非甲基化 CpG 丰富启动子的基因的转录。CpG 的非甲基化状态通常在从母细胞到子细胞的细胞分裂过程中得到维持。因此，MOZ/MLL 介导的转录激活系统通过激活在母细胞中先前转录的基因的转录，在子细胞中复制母细胞的表达谱。这篇综述总结了 MOZ/MLL 介导的转录激活系统的组成部分的功能及其在促进自我更新中的作用。
